Prevalence of Drug Resistant Influenza B Viruses: New Findings and Implications
By Richard Waldhorn, M.D., April 13, 2007
In a study published in the April 4, 2007 edition of the Journal of the American Medical Association (JAMA), Hatakeyama and colleagues report on the emergence of influenza B viruses that are partially resistant to neuraminidase inhibitors. These viruses were found in a population of people in Japan who were not previously treated with antiviral agents. The researchers’ analysis indicates that these partially resistant viruses were likely acquired through person to person transmission in a community or through contact with infected siblings . In an accompanying editorial, Moscona and McKim-Breschkin discuss the implications of these findings. 
The neuraminidase inhibitors zanamivir and oseltamivir are used extensively in Japan. Hatakeyama and others have documented the emergence of oseltamivir resistant influenza A viruses. Recent studies of influenza A viruses reveal that 18% of children with H3N2 infection and 16% of those with H1N1 infection had neuraminidase resistant variants after treatment with oseltamivir [3, 4]. The infectivity and transmissibility of neuraminidase resistant viruses appears to differ depending upon the type of mutation present in the neuraminidase. Hatakeyama’s study analyzed the prevalence, transmissibility, and genetic sequences of drug resistant variants during the winter 2004-2005 influenza B epidemic in Japan.
Pharyngeal or nasal swabs for influenza B virus were obtained from patients visiting pediatric services at 4 community hospitals during the 2004-2005 influenza season. Paired samples were taken from 74 patients before and during treatment with oseltamivir in an attempt to identify the frequency with which oseltamivir resistant influenza B viruses developed. From those samples, 65 viral isolates were obtained during oseltamivir therapy and evaluated for IC50.
Pretreatment viral isolates were obtained from an additional 282 children and 66 adults with influenza B infection and were pooled with 74 pretreatment viral isolates from the paired analysis. All 422 pretreatment viral isolates were evaluated for IC50 to assess prevalence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors in a community setting. Neuraminidase and hemagglutinin genes of viruses showing reduced sensitivity to neuraminidase inhibitors were sequenced to identify mutations.
In the analysis of paired samples before and during treatment with oseltamivir in 74 children, 1 isolate (1.4%) with reduced sensitivity to neuraminidase inhibitors developed 3 days after initiation of therapy
The analysis of pretreatment samples identified variants with reduced sensitivity to both oseltamivir and zanamivir in 7 of 422 patients (1.7%). In two siblings, reduced-sensitivity isolates revealed identical sequence analysis of the neuraminidase and hemagglutinin genes suggesting transmission within the family
In the pretreatment group, another patient with a drug resistant isolate had a sibling who had been documented to have a wild type influenza virus and was then subsequently treated with oseltamivir. Although post treatment isolates were not available, genetic analysis revealed identical sequences except for the single amino acid substitution in the resistant isolate. The authors suggest that a drug resistant virus might have developed in the oseltamivir treated sibling and later been transmitted to her sister.
Four patients with pretreatment mutations with reduced sensitivity to neuraminidase inhibitors did not have family members with influenza B virus infection prior to the onset of their illness, suggesting that person to person transmission may have occurred in the community and not just with close family contacts.
The clinical course of patients with resistant Influenza B viruses was similar in terms of duration of fever and the extent of viral shedding.
The key findings of this report are that influenza B viruses with reduced sensitivity to neuraminidase inhibitors can emerge during therapy, circulate in families and the community, and be transmitted, causing clinical infection that is not different from infection with wild type virus.
The authors of the accompanying editorial explain that past complacency about neuraminidase resistant influenza may have to be re-evaluated in light of these findings. They point out that modeling studies for pandemic influenza based on the use of antiviral agents to limit transmission have concluded that community spread of resistant viruses would not be significant because of decreased biological fitness and transmissibility of these variants . The demonstration that influenza B viruses with reduced sensitivity to neuraminidase inhibitors can be found in the community and can be transmitted suggests that it may no longer be safe to assume that resistant viruses would not have an impact in a pandemic.
Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA. 2007 Apr 4; 297(13):1435-42.
Moscona A, McKimm-Breschkin J. News about influenza B drug resistance that cannot be ignored. JAMA. 2007 Apr 4;297(13): 1492-3.
Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364:759-765.
Ward P, Small I, Smith J, et al. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005;55(suppl 1):i5-i2l.